PROJECT SUMMARY ? ABSTRACT Type 1 Diabetes (T1D) is a chronic autoimmune disease targeting the insulin-producing pancreatic ? cells. While autoantibodies (AAb) against ? cell antigens serve nicely as predictive biomarkers for T1D development, current diagnostic definitions of presymptomatic T1D additionally require time consuming and invasive glucose tolerance testing. Thus, a need exists for additional serum biomarkers reflective of metabolic and/or immunologic dysregulation which may be tested concurrently with AAb screening. Additionally, while impairments in immune regulation are known to permit ? cell destruction, the factors contributing to these mechanisms are incompletely defined. My overall goal is to identify a clinically relevant pathway that may be monitored and targeted during pre-T1D. The insulin-like growth factor (IGF) family, comprised of immune and metabolism-altering hormones, should therefore be evaluated in terms of biomarker potential during T1D development and contribution to T1D- specific immune impairments. This family is comprised of two ligands, IGF1 and IGF2, as well as IGF binding proteins (IGFBP), which limit IGF availability. IGFs have been shown to possess anti-inflammatory effects including promotion of regulatory T cell (Treg) function and reduction of antigen presentation. Therefore, I hypothesize that IGF1 and IGF2 levels or bioavailability are reduced in the development of T1D and that this contributes to impairments in immune regulation that culminate in ? cell destruction. The innovation of this research lies in extending the knowledge of a well-characterized axis of proteins with increased expression in cancer toward an autoimmune context. To date, the majority of the IGF family remains uncharacterized in pre- T1D. I propose to assess the levels of these factors longitudinally in the non-obese diabetic mouse model as compared to diabetes-resistant controls as well as cross-sectionally in human cohorts with varying risk for development of T1D. Importantly, my preliminary data shows that IGF1 and IGF2 are reduced in AAb+ at-risk relatives of T1D patients as compared to age-matched AAb- lower-risk counterparts. Currently, IGFBP levels in pre-T1D are uncertain, so IGF availability remains unclear. The basis for anti-inflammatory effects of IGFs is also ambiguous, as no direct evidence exists of the preferential promotion of Treg over conventional T cell (Tconv) proliferation and function. Therefore, I propose to discern the impact of IGFs on human Treg and Tconv proliferation, activation, cytokine production, and metabolism. Lastly, while IGFs have been suggested to limit antigen presentation, I propose to assess how this specifically impacts the human ? cell to modulate recognition and ultimately killing by antigen-specific T cells. The significance of this work lies in the potential for application toward clinical diagnostics of pre-T1D and therapeutics to restore the regulatory/effector balance and limit islet- intrinsic promotion of inflammation.